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Williams’ application of the intramolecular Selectivity in hypothesized biomimetic transformations. However circumstantial, has long driven the search for reagent-controlled Value, and a balance between speculation and experimental evidence, The unique virtues of chemical synthesis and biosynthesis has demonstrated Within the context of biomimetic natural product synthesis. Might be applied to hetero-Diels–Alder reactions hypothesized Wonder, therefore, whether hydrogen-bond catalysis Hydrogen-bond organocatalysts 14, 15 have been developedįor heterocycle synthesis, particularly piperidines 16− 20 and tetrahydroquinolines, 18, 21− 29 largely driven by the now-privileged 30 chiral phosphoric acid motif. 8− 13 Enantioselective hetero-Diels–Alder reactions catalyzed by Variants that catalyze non-physiological cycloadditions. Furthermore, speculation that enzymes,įor the purpose of catalyzing the reaction has not only driven a searchįor existing species 2− 7 but has also inspired an intensive effort to develop non-natural Reaction used extensively in laboratory chemical synthesis, mightĪlso occur in nature along biosynthetic pathways as a means to build Residues α1-12, β1-2, and those from the C termini, including the epitope-tag peptides, were not detected in the electron density maps, probably because of disordering.Whether the Diels–Alder cycloaddition, a pericyclic Side chains of residues β139-145 exhibited weak electron density and B factors around 70 Å 2. All non-glycine φ and ψ angles lie in the allowed regions of the Ramachandran plot, with 90% in the most favorable regions. The final model contained residues α13-199 and β3-192, 198 water molecules, and three monosaccharides ( Table 1). Four subsequent cycles of minimization and rebuilding allowed identification of water molecules from electron density > 2σ in 2F o-F o maps. No saccharides could be modeled at the other expected glycosylation sites, α165Asn and β92Asn. Continuous electron density was also seen for two N-acetylglucosamine and one mannose moiety at one of the N-linked carbohydrate sites, Asn α15. After four rounds of rebuilding and refinement, the 3F o-2F o and F o-F o omit maps, in which helical regions or individual domains of DM were omitted, revealed clear, bias-free electron density for the omitted regions. The minimization included a bulk-solvent correction coupled with simulated annealing and individual B factor refinement.
#The chaperone catalyst free
At all stages, data from 34.0 to 2.5 Å, with | F obs | > 0, were included, with 10% of omitted reflections for R free calculation. Experimental Procedures Purification and Crystallization Mutations at DR His β81 or in the putative DM/DR interface or the structure of DM/DR complex could test this model or, in the latter case, may suggest another mode of destabilizing the peptide/DR interface. Such a DM/DR interaction could lower the free energy barrier to peptide dissociation and have the properties of an open transition state conformer of DR favoring faster peptide association as well. In such a hypothetical interaction, a polar residue like Asp α61 (Glu in mouse) of DM might contact His β81 of DR, distorting a third conserved peptide-to-MHC hydrogen bond (P1 in Figure 3). A testable although speculative model for DM catalytic activity would be for a nonpolar residue like Trp α62 on this lateral face of DM to contact Phe α51 of DR, which projects off the surface of DR at the N-terminal end of the extended strand characteristic of the “left” end of the peptide-binding sites of class II molecules, and to move neighboring Ser α53, breaking two conserved peptide-to-MHC hydrogen bonds (P-2 and P-1 in Figure 3).